Making Decisions about the Risks of Chemicals in Foods with Limited Scientific Information_IFT Expert Report 2009

Making
Decisions about
the Risks of
Chemicals in
Foods with
Limited
Scientific
Information
An IFT Expert Report Funded by the IFT Foundation

ABSTRACT: On occasion, food safety managers may detect an undesirable chemical contaminant or unanticipated
chemical substance in a food commodity, ingredient, or finished product, thereby warranting an assessment of the
health impact of the substance at the level detected. Many times, such an assessment must be made with limited
scientific information. In such situations, food safety managers must expeditiously evaluate the available data and
other information and make decisions such as whether to implement a food product recall to protect public health
and maintain integrity of and confidence in the food supply.
Under such circumstances, making decisions about risk can be very complicated by the interactions of a number
of issues. Interpretation of scientific and public policy can cause confusion as a result of insufficient data for con-
ducting a risk assessment, conflicting data, uncertainty stemming from toxicological issues or temporal constraints,
emerging nature of the state of the science, and regulatory constraints (for example, zero tolerance). A user-friendly
conceptual framework would aid food safety managers faced with making decisions about the risks of newly de-
tected, undesired chemical substances in foods—whether naturally occurring toxins, direct or indirect food addi-
tives, substances arising through food processing, or other substances.
The Institute of Food Technologists (IFT) convened a group of experts to (1) examine the complexities that challenge
timely decision-making about such substances when available scientific information is limited and (2) define and
develop a workable tool to guide food safety managers in effectively and knowledgeably evaluating available scien-
tific evidence pertinent to assessing the risk from exposure to a chemical substance to make timely decisions. This
Expert Report delves into the legal U.S. underpinnings of the risk management of chemical substances in foods,
international considerations, risk-benefit evaluation, importance of the food matrix to risks and benefits, risk as-
sessment and management, and the need for a new approach to timely decision-making with limited scientific in-
formation. This report includes case studies that demonstrate (1) the various complexities and how sound decision-
making with sufficient available pertinent data is reinforced as additional supportive data subsequently become
available and (2) the importance of assessing and balancing consideration of risks and benefits from a whole food
perspective.

Contributors Wayne R. Bidlack, Ph.D.
IFT selected the following contributors to this Expert Re- Professor, Dept. of Human Nutrition & Food Science
port for their valuable, pertinent scientific expertise. Their California State Polytechnic Univ.
contributions represent their individual scientific perspectives Diane Birt, Ph.D.
and do not necessarily represent the perspectives of their Distinguished Professor, Dept. of Food Science & Human
employers. Nutrition

C 2009 Institute of Food Technologists R Vol. 8, 2009—COMPREHENSIVE REVIEWS IN FOOD SCIENCE AND FOOD SAFETY 269

CRFSFS: Comprehensive Reviews in Food Science and Food Safety
Director, Center for Research on Botanical Dietary Martin Slayne, Ph.D.
Supplements Director, Intl. Food Safety & Nutrition
Interim Director, Nutrition & Wellness Research Center PepsiCo Intl.
College of Agriculture & Life Sciences
College of Human Sciences Thomas Trautman, Ph.D.
Iowa State Univ. Fellow, Toxicology & Regulatory Affairs
General Mills Inc.
Joseph Borzelleca, Ph.D.
Professor Emeritus IFT Staff
Toxicology & Pharmacology Inc.
Rosetta Newsome, Ph.D.
Roger Clemens, Ph.D. Director, Science and Communications
USC School of Pharmacy
Adjunct Professor, Pharmacology and Pharmaceutical Sciences Toni Tarver
Associate Director, Regulatory Science Scientific and Technical Communications Manager
Nicole Coutrelis Additional Acknowledgments
Partner
Coutrelis & Associates Cory Bryant, Ph.D.
General Health Scientist, Food and Drug Administration
James R. Coughlin, Ph.D. Office for Food Defense, Communication, and Emergency
President Response
Coughlin & Associates Food Defense Oversight Team
George E. Dunaif, Ph.D., D.A.B.T. Fred Shank, Ph.D.
Vice President, Global Food Safety Retired
Global Research & Development Institute of Food Technologists
Campbell Soup Co.
Andrew Ebert, Ph.D. Reviewer
President Steve Taylor, Ph.D.
ETM Inc. Professor
Richard Hall, Ph.D. Univ. of Nebraska
Past President, IFT
Past President, Intl. Union of Food Science and Technology Introduction
James T. Heimbach, Ph.D., F.A.C.N. Safety has no mixed connotation and, as it applies to food
President and health, is nonnegotiable. The food industry views food safety
JHeimbach LLC as its highest priority. Cooperation among producers, ingredient
suppliers, food scientists, processors and other food technolo-
William Helferich, Ph.D. gists, distributors, and federal, state, and local regulatory officials
Professor of Nutrition, Food Science & Human Nutrition is critical in ensuring the safety of the global food supply and
Univ. of Illinois maintaining consumer trust and confidence. There have been
Bernadene Magnuson, Ph.D. many efforts to improve risk assessment. Virtually all of them
Senior Scientific & Regulatory Consultant stress the importance of acquiring additional data. In contrast,
Cantox Health Sciences Intl. this report deals with risk assessment on the basis of currently
available and often less than adequate data. Facing the dilemma
Diane B. McColl, Esq. of the need to make a decision about the level of risk presented
Principal by a chemical substance associated with food, perhaps arising
Hyman, McNamara, and Phelps, P.C. through the discovery of traces of a chemical, with limited or less
Robert S. McQuate, Ph.D. than a desired amount of data triggers a host of questions: Is it
CEO & Co-Founder safe? How did it get in the food? What can be done? What should
GRAS Associates, LLC be done? According to the Toxic Substances Control Act list by
Ian Munro, Ph.D., F.A.T.S., FRCPath the U.S. Environmental Protection Agency (EPA), there are more
Executive Vice President and Senior Science Consultant than 75000 known chemicals in our environment, many of which
Cantox Health Sciences Intl. may come in contact with food via soil, air, or water. The pres-
ence of chemicals such as acrylamide and polycyclic aromatic
Barbara Petersen, Ph.D. hydrocarbons (PAHs), which form upon normal food preparation
Practice Director and Principal Scientist and heating, may be discovered through advances in analytical
Food and Chemicals Practice methods and techniques. Other chemical substances may be in-
Exponent Inc. tentionally added, such as direct food additives, unintentionally
Ashley Roberts, Ph.D. added, such as indirect food additives migrating from packaging
Vice President, Food & Nutrition components to food, naturally occurring or more deliberative,
Cantox Health Sciences Intl. arising from accidental contamination or malicious adulteration.
Product safety is the foundation of consumer trust. However,
Joseph Scimeca, Ph.D. consumer trust in the food supply can be undermined by food
Director, Global Regulatory Affairs recalls, which may sometimes constitute the end stage of food
Corporate Food Safety & Regulatory Affairs safety assessments and decision making. An online poll of 2563
Cargill adults indicated that almost 8 in 10 adults (79%) are aware of food
270 COMPREHENSIVE REVIEWS IN FOOD SCIENCE AND FOOD SAFETY—Vol. 8, 2009

Making decisions about the risks of chemicals in foods . . .

recalls in the United States (Harris Interactive 2007). Moreover, is subject to a civil seizure action in a U.S. district court, and
more than 86% of those polled mentioned at least some concern corporations or individuals responsible for introducing adulter-
with food recalls, and 29% indicated that food recalls were a ated food into interstate commerce food are subject to an in-
serious concern. junction proceeding and/or to criminal prosecution in the U.S.
Food safety issues quickly become news that is rapidly dissem- district courts. A food may be deemed adulterated for a num-
inated to distant regions and countries at the speed of an e-mail ber of different reasons, the following of which are relevant to
or broadcast journalist’s report. While they are the most public this report:
aspect of apparent food safety failures, food recalls is just 1 com- r the presence of any poisonous or deleterious substance that
ponent of the complicated food safety decision-making process. may render a food injurious to health unless the substance is
Critical and challenging decisions are made prior to a recall. not an added substance and present in an amount that does
However, real-time information is difficult to obtain and is often not ordinarily render it injurious to health;
limited and/or difficult to interpret. Undertaking food chemical r the presence of any unavoidable added poisonous or deleteri-
safety assessments requires detailed knowledge of the chemistry ous substance, other than a pesticide residue, a food additive,
and toxicology of the substances in question. Invariably, deficien- a color additive, or a new animal drug unless the quantity of
cies or gaps in the underlying science become evident. The con- such substance does not exceed an applicable FDA-designated
text of the level of exposure to a chemical substance in question tolerance level;
also is critical in making meaningful interpretations of available r the presence of a pesticide chemical residue at levels that
information. This is particularly true when confronted with defi- exceed an applicable tolerance level or that is not subject to
ciencies and gaps in available scientific data. Consequently, the an exemption;
decision-making process in making food safety assessments can r the presence of an unapproved food additive or unapproved
be very difficult. color additive;
This report has 3 main sections. The first section sets forth the r the presence of a new animal drug (or conversion product
U.S. legal framework and international institutions and measures thereof) unless the drug residue falls within an applicable tol-
that govern the safety of the food supply. The 2nd section deals erance for such drug;
with risk analysis—that is, how the nature and size of real or po- r the dietary supplement or a dietary ingredient therein that
tential risks are determined or, more frequently, estimated. This presents a significant or unreasonable risk of illness or injury
section discusses in some detail ways to use the available infor- under recommended or labeled conditions of use, or if no such
mation to best advantage, especially when that information is recommendations or labeling, under normal conditions of use;
less complete than desirable. And the third section of the report or
covers how that information on the nature, size and probability r failure to submit to FDA a new dietary ingredient premarket
of a risk can be applied in making appropriately conservative notification at least 75 days prior to marketing a dietary sup-
and balanced decisions. This section particularly emphasizes the plement containing a new dietary ingredient that has not been
need to weigh carefully information about the risk(s) of an un- present in the food supply as an article used for food in a form
avoidable food component against the benefits of the food(s) in in which the food has not been chemically altered (21 USC
which that component is found. §§ 331–333, 342, 350b).
For the purpose of this report, the term “risk” is defined as “the The intended use of an item determines its regulatory status
possibility of loss, injury, disadvantage, or destruction” (Gove under the FD&C Act, and its regulatory status dictates the stan-
1993). Risk is not the reality of being deprived or in a state of dard that is to be applied in evaluating its safety. Whether an
disadvantage; instead, it is the threat of becoming so. Health article is regulated as a food or falls within a different regulatory
risks are a subset of what are often called vital risks because they classification depends on its intended use, rather than its source,
have a major impact on life itself. Similarly, the term “benefit” biochemical composition, or ingestive status. Items classified as
is “something that guards, aids, or promotes well-being” (Gove food are presumed safe, and the FDA bears the burden of estab-
1993). Secondary meanings connote something good, or produc- lishing by a preponderance of the evidence that a particular food
ing a positive outcome. Thus, the terms “risk” and “benefit” are is injurious to health. However, this presumption of safety does
not opposites: Risk always and explicitly includes the element of not extend to most food components, the vast majority of which
chance; benefit does not. fall into specific regulatory classifications with attendant safety
standards that must be met by manufacturers. Such food com-
ponents include food additives, color additives, processing aids,
U.S. Legal Framework substances that migrate into food from processing equipment or
An extensive legal framework involving key federal statutes, packaging materials, dietary ingredients in dietary supplements,
such as the Federal Food, Drug and Cosmetic (FD&C) Act, pro- pesticide residues, and animal drug residues. Circumstances re-
vides a strong foundation for U.S. food safety policy and deci- quiring expert decision-making with respect to the safety of a
sion making that incorporates precaution and science-based risk food or food component range from the introduction of a new
analyses (FDA-USDA 2000). This report focuses on food safety food ingredient or a new food use to the presence of an un-
decision-making relating to chemical substances; thus, the legal approved food additive or color additive and the intentional or
framework presented herein excludes aspects of the regulatory unintentional addition of a contaminant. (See 21 USC § 321 (f);
authority for meat and poultry by the U.S. Dept. of Agriculture Nutrilab Inc. v. Schweiker, 713 F.2d 335, 337–8 (7th Cir. 1983);
(USDA). This report also does not address the legal framework Jones v. Rath Packing Co. 430 US 519 (1997); U.S. v. O.F. Bayer
for rDNA biotechnology-derived foods (see the IFT Expert Report & Co., 188 F.2d 555 (2nd Cir. 1951).)
“Biotechnology and Food” for information on biotechnology).
The safety of food products other than meat, poultry, and cer- Introduction of new substance, new use
tain egg products is regulated in the United States by the FD&C The Food Additives Amendment of 1958 added food addi-
Act, as interpreted and applied by the FDA and, on occasion, tive provisions to the 1958 FD&C Act. The amendment es-
federal courts. The FD&C Act prohibits introducing any food that tablished a broad definition for food additives and required
is adulterated into interstate commerce and the adulteration of FDA premarket approval of such substances. Exempted from
any food already in interstate commerce. An adulterated food food additive status were substances used in accordance with a
Vol. 8, 2009—COMPREHENSIVE REVIEWS IN FOOD SCIENCE AND FOOD SAFETY 271

sanction or approval granted by either the FDA or the USDA that food into a food additive perverts the statutory text, under-
prior to the enactment (known as prior-sanctioned substances), mines legislative intent, and defenestrates common sense.” (See
generally recognized as safe substances (commonly referred to as U.S. v. Two Plastic Drums . . . Vipointe Ltd, 984 F.2d 814 (7th
GRAS substances), color additives, pesticide chemical residues, Cir. 1993); U.S. v. 29 Cartons . . . an Article of Food (Oakmont
pesticide chemicals, and new animal drugs. The Dietary Supple- Investments), 987 F.2d 33, 35 (first Cir. 1993).)
ment Health and Education Act (DSHEA) of 1994 later exempted The FD&C Act provides that the FDA shall issue no food addi-
certain dietary supplement ingredients from the food additive tive regulation if “a fair evaluation of the data . . . fails to establish
definition. Of the substances exempted from regulation as food that the proposed use of the food additive, under the conditions
additives, only prior-sanctioned substances, GRAS substances, of use to be specified in the regulation, will be safe” (21 U.S.C.
and certain dietary supplement ingredients do not require FDA § 348(c)(3)(A)). This is the general safety standard applied to food
approval or notification prior to use. However, exemption from additives. For this purpose, the FDA defines safe as “a reasonable
food additive status does not exempt a substance from other pro- certainty in the minds of competent scientists that the substance
visions of the FD&C Act relating to safety. If the FDA were to con- is not harmful under the intended conditions of use” (21CFR
clude that a substance, which was prior-sanctioned or believed § 170.3(i.)). The FDA recognizes that “it is impossible in the
to be GRAS at a time when certain risks were not perceived, sub- present state of scientific knowledge to establish with complete
sequently became known to be dangerous for use, the agency certainty the absolute harmlessness of the use of any substance”
could object to use of the substance as an added poisonous or (21 CFR § 170.3(i)). In its risk assessment of food additives, the
deleterious substance. FDA must consider, among other relevant factors, the estimated
Food additives. The FD&C Act defines a food additive as “any consumption of the additive and of any substance formed in foods
substance the intended use of which results or may reasonably be due to use of the additive, the cumulative effect of such sub-
expected to result, directly or indirectly, in its becoming a compo- stances and any chemically or pharmacologically related sub-
nent or otherwise affecting the characteristics of any food . . . , if stances in the diet, and the appropriate safety factors for inter-
such substance is not generally recognized, among experts qual- pretation and extrapolation of animal data. In applying animal
ified by scientific training and experience to evaluate its safety, experimental data to man, the FDA typically uses a safety factor
as having been adequately shown through scientific procedures of 100 unless scientific evidence justifies a different safety factor
(or, in the case of a substance used . . . prior to January 1, 1958, (21 CFR § 170.22).
through either scientific procedures or experience based on com- The 1958 amendment added the food additive Delaney Clause,
mon use in food) to be safe under the conditions of its intended which is also known as the anti-cancer clause, to the FD&C. The
use” (21 USC § 321(s)). food additive Delaney Clause provides that no food additive shall
A substance that may become a component of food, either be deemed safe if “it is found to induce cancer when ingested by
directly or indirectly, is regulated as a food additive unless the man or animal, or if it is found, after tests which are appropriate
substance is considered a GRAS substance or falls within a cat- for the evaluation of the safety of food additives, to induce cancer
egory of substances exempt from regulation as food additives. in man or animal” (21 USC § 348(c)(3)(A)). The FDA has no
Use of a food additive is prohibited unless FDA first approves the discretion to permit use of a food additive for human food use
substance and publishes a regulation prescribing the conditions once a finding of carcinogenicity is made regardless of the degree
under which the additive may be safely used in foods (21 USC §§ of risk involved. However, the Delaney Clause applies to the food
331, 342, 348). additive itself and not to constituents of the additive. As the FDA
The practical effect of classifying a product as a food addi- has acknowledged, if a food additive has not been shown to
tive rather than a food is twofold: (1) FDA premarket approval is cause cancer even though it contains a carcinogenic impurity,
required, and (2) the burden shifts to the manufacturer to demon- then the food additive Delaney Clause does not apply and the
strate safety. Predictably, disputes have arisen as to whether a par- additive is properly evaluated under the general safety standard
ticular product constitutes a food or a food additive. The courts using risk assessment procedures to determine whether there is a
have held that whether a substance is a food additive is not de- reasonable certainty that no harm will result from the proposed
pendent on quantity. Substances present in both large and small use of the additive (FDA 2003). (See Les v. Reilly, 968 F.2d 985
quantities can be food additives, and a substance may be both (9th Cir. 1992); Scott v. FDA, 728 F.2d 322 (6th Cir. 1984)).
a food and a food additive regardless of whether the substance GRAS substances. GRAS substances are not regulated as food
ordinarily would be considered a food. additives and do not require FDA approval prior to use. Shortly
However, not every component of food is a food additive. In after enactment of the 1958 amendment to the FD&C Act, FDA
the court case U.S. v. Two Plastic Drums . . . Vipointe Ltd, black published a list of many, but not all, substances believed to be
currant oil was encased in a capsule made from gelatin and glyc- GRAS for use in food (FDA 1958, 1959). These regulations are
erin to facilitate swallowing. Seeking to condemn the component, known informally as the FDA’s GRAS list. However, the agency
the FDA claimed that the black currant oil was a food additive be- explicitly recognizes that it is impracticable for the FDA to pub-
cause the combination of black currant oil, glycerin, and gelatin lish regulations identifying all substances that are GRAS for use
created a food and merely being a component of food rendered in food. The FDA also acknowledges that “a substance that is
the black currant oil a food additive. The 7th Circuit U.S. Court GRAS for a particular use may be marketed for that use with-
of Appeals disagreed with the FDA’s broad interpretation of the out agency review and approval” (FDA 1997). Additionally, FDA
food additive definition, subsequently concluding that “to be a recognizes that companies “have the right to make independent
food additive, a substance must not only be added to food, but it GRAS determinations on food substances” (FDA 1988). Manu-
must also have the purpose or effect of altering a food’s charac- facturers may notify the FDA of their GRAS determinations, but
teristic” (Vipointe at 818). Shortly thereafter, the first Circuit U.S. such notifications are completely voluntary (FDA 1997). (See 21
Court of Appeals confronted the issue again in the court case CFR Parts 182, 184, and 186; 21 CFR §§ 170.30(d), 182.1(a).)
U.S. v. 29 Cartons . . . an Article of Food (Oakmont Investments), A determination of the GRAS status of the use of a substance
which also involved capsules of black current oil, finding that the may be based either on common use in food prior to January 1,
gelatin capsule itself was not a food additive within the meaning 1958 or on scientific procedures. Establishment of GRAS status
of the FD&C Act. The court wrote, “The proposition that placing a through common use is ordinarily based on generally available
single-ingredient food product into an inert capsule . . . converts data and information and does not require the same quantity or


quality of scientific evidence needed for food additive approval. is convincing evidence that establishes with reasonable certainty
The common use in food may occur outside of the United States, that no harm will result” from such use in foods (21 CFR § 70.3(i)).
provided that documentation and independent corroboration of Among other factors pertinent to safety, the FDA must consider
such use is both widely available in the country of use and readily the probable consumption of the color additive or any substances
accessible to interested, qualified scientific experts in the United formed in food from the additive; the cumulative effect, if any, of
States. However, in Fmali Herb Inc. v. Heckler, the 9th Circuit the additive in the diet of man or animals, taking into account
U.S. Court of Appeals cautioned that “evidence of foreign use of background dietary exposure and chemically or pharmacologi-
an ingredient, standing alone, may rarely or never be enough to cally related substances; appropriate safety factors for application
establish safety.”(See 21 CFR §§ 170.35(c)(1), 170.35(c)(2); Fmali of animal data; and availability of practicable methods of analysis
Herb Inc. v. Heckler, 715 F.2d 1385, 1390–1 (9th Cir. 1983)). for identifying and quantifying the color additive in foods. (See
Establishing GRAS status through scientific procedures requires 21 USC §§ 342(c), 379(e), 379e(b)(4),379e(b)(5).)
both technical evidence of safety and evidence of common The Color Additive Amendment included an anti-cancer De-
knowledge or general recognition among qualified experts. As to laney Clause for color additives. The clause states that an additive
technical evidence of safety, the FDA’s position is that “a GRAS shall be deemed unsafe and shall not be listed by the FDA if the
substance is neither more nor less safe than an approved food ad- additive is found “to induce cancer in man or animal.” No de
ditive” (FDA 1997). Therefore, the same quantity and quality of minimis exception to the color additive Delaney Clause exists;
scientific evidence is required (at least in theory) to demonstrate once a color additive has been found to induce cancer in man
safety of a substance that is GRAS based on scientific procedures or animal, the FDA cannot list the additive for use in human
as is required for a food additive. The common knowledge ele- foods even if exposure to the substance in foods would present
ment is an important distinguishing factor between a substance a toxicologically insignificant trivial risk. The courts have up-
that is GRAS based on scientific procedures and a safe food addi- held the FDA’s interpretation of this clause as applicable only
tive. To satisfy the common knowledge requirement, the data and to the color additive as a whole, not to its carcinogenic impuri-
information relied on to establish the safety of the substance must ties. Thus, the FDA may approve a color additive shown not to
be generally available to the scientific community, and there must cause cancer even though the additive contains trace amounts
be a basis to conclude that a consensus exists among qualified of a known carcinogenic impurity. The FDA will evaluate such
experts about the safety of the substance for its intended use. (See substances applying risk assessment methods under the general
21 CFR § 170.30(b).) safety clause. (See Public Citizen v. Young, 831 F.2d 1108 (D.C.
A conclusion that a substance is actually safe is not sufficient to Cir. 1987); Scott v. FDA, 728 F.2d 322 (6th Cir. 1984); 21 USC
support the GRAS status of a food ingredient. Rather, the conclu- § 379e(b)(5)(B).)
sion of safety must be supported by evidence that the substance A DES Proviso exception for colors used in feed for food-
is generally recognized among experts as safe under the condi- producing animals was added to the color additive Delaney
tions of intended use. While unanimity is not required, there must Clause by the 1962 Drug Amendments. The DES Proviso excep-
be evidence of a consensus among qualified experts and pivotal tion allows the FDA to approve a color shown to induce cancer
safety data must be publicly available. In this respect, it is a much when ingested by man or animal for use in an animal feed only if
higher standard than the general safety standard applied to food 2 conditions are met: the color must not adversely affect animals
additives. (See United States v. An Article of Food . . . Coco Rico consuming the colored feed, and FDA-approved or prescribed
Inc., 725 F.2d 11 (first Cir. 1985); United States v. Articles of analytical methods would find no residue of the color in edible
Food . . . Coli-Trol, 518F.2d 743 (5th Cir. 1975); United States v. portions of the animal after slaughter or in food yielded by or
Articles of Food . . . Sodium Pangamate, (1978 to 1979 Transfer derived from the living animal. (See 21 USC § 379e(b)(5)(B).)
Binder) Food Drug Cosm. L. Rep. (CCH) ¶ 38,226.) Food contact materials. Without an established GRAS status or
Color additives. The Color Additive Amendment of 1960 added a prior sanction for the intended use, a substance present in food
FDA premarket approval and, for certain dyes, certification, re- contact materials that could reasonably be expected to migrate
quirements to the FD&C Act. A color additive is defined in the into foods may be regulated as a food additive requiring FDA pre-
FD&C Act as a material that market approval. However, most substances used in food contact
r is a dye, pigment, or other substance made by a process of materials are not regulated as food additives. In 1979, the U.S.
synthesis or similar artifice, or extracted, isolated, or other- Court of Appeals for the District of Columbia Circuit held that
wise derived, with or without intermediate or final change of the FDA must determine with a fair degree of confidence that
identity, from a vegetable, animal, mineral, or other source, such a substance migrates into food in more than insignificant
and amounts to regulate it as a food additive (Monsanto v. Kennedy,
r when added or applied to a food . . . is capable (alone or 613 F.2d 947 (D.C. Cir. 1979)). The court noted that the FDA may
through reaction with other substance) of imparting color decide, based on scientific evidence, that the level of migration
thereto: except that such term does not include any material into food of a particular chemical is so negligible or de minimis
which (FDA), by regulation, determines is used (or intended as to present no public health or safety concern (Monsanto v.
to be used) solely for a purpose or purposes other than color- Kennedy at 955). In subsequent notice-and-comment rulemak-
ing. . . . The term color includes black, white, and intermediate ing, the FDA concluded that numerous food additives used in the
grays. (See 21 USC §321(t).) production of food contact articles would be expected to migrate
There are no exemptions from the color additive definition, and to foods at trivial levels presenting no safety concerns and estab-
GRAS does not apply to color additives. Even if a color additive lished a procedure for granting a threshold of regulation (TOR)
is generally recognized among qualified experts as safe for use as exemption from food additive regulation, thereby exempting such
a color additive, it must first be approved and listed by the FDA substances from the premarket approval requirement (FDA 1993,
before it may be used as a color additive in food. 1995). A TOR exemption will be granted if “the substance has not
The FD&C Act provides that the FDA “shall not list a color been shown to be a carcinogen in humans or animals, and there
additive for a proposed use unless the data before (the FDA) es- is no reason, based on the chemical structure of the substance, to
tablish that such use, under the conditions of use specified in the suspect that the substance is a carcinogen.” In addition, the sub-
regulations will be safe . . . ” (21 USC § 379e(b)(4)). For purposes stance may not contain any carcinogenic impurities, or if it does,
of determining safety of a color additive, safe means that “there the impurity must have a TD 50 (the dose that causes cancer in

50% of test animals) of less than 6.25 mg/kg body weight/d. The of an important adverse health effect to a user may be unreason-
intended use of the substance must result in dietary concentra- able” (FDA 2004). However, the agency acknowledged that some
tions ≤ 0.5 parts per billion (≤1.5 μg/person/d), or if it is already evidence of risk is required to meet this standard.
approved by FDA for direct addition to food, the dietary expo- A dietary ingredient not marketed in the United States before
sure must be less than 1% of the FDA’s acceptable daily intake October 15, 1994, is considered a new dietary ingredient. A di-
(or ADI). Finally, the substance may not have any technical effect etary supplement containing a new dietary ingredient is deemed
in or on the food to which it migrates, and the substance must adulterated unless either (1) the supplement “contains only di-
not adversely affect the environment. (See Monsanto v. Kennedy, etary ingredients which have been present in the food supply
613 F.2d 947 (D.C. Cir. 1979); 21 CFR §§ 170.39, 170.39(a)(1), as an article used for food in a form in which the food has not
170.39(a)(2), 170.39(a)(3)–(4), 174.6.) been chemically altered,” or (2) there is a “history of use or other
The FDA Modernization Act of 1997 amended the FD&C Act evidence of safety establishing that the dietary ingredient when
to create a premarket notification (FCN) procedure as the primary used under the conditions recommended or suggested in the la-
method by which the FDA regulates substances that are used in beling . . . will reasonably be expected to be safe” (21 USC §
production of food contact materials. The FD&C Act defines a 350b(a)). In the latter case, the manufacturer or distributor of the
food contact substance as any substance intended for use as a dietary ingredient or dietary supplement must, 75 days prior to
component of materials used in manufacturing, packing, pack- marketing, submit to the FDA information (including citations to
aging, transporting or holding food if such use is not intended to any published articles) that constitutes the basis upon which the
have any technical effect in such food. (See 21 USC §§ 348(h), manufacturer or distributor concludes that a product will reason-
348(h)(6); 21 CFR §§ 170.100-170.106.) ably be expected to be safe. (See 21 CFR § 190.6.)
The FD&C Act states that the FCN process shall be used for In addition, a dietary supplement or dietary ingredient therein
authorizing the marketing of a food contact substance unless the may also be deemed adulterated if the Secretary of the Dept. of
FDA determines that submission of a food additive petition is Health and Human Services declares that it poses an imminent
necessary to provide adequate assurance of safety. The FDA may hazard to public health or safety. The authority to declare a di-
require a food additive petition if (1) the use of the FCN increases etary supplement to be an imminent hazard must be exercised by
cumulative daily dietary concentration to 200 ppb (0.6 mg/ the secretary and may not be delegated to the FDA. The secretary
person/d) or more for a biocide or to 1 ppm (3 mg/person/d) must thereafter promptly hold a formal hearing to assemble data
or more for a nonbiocide, or (2) there exists a bioassay of the “to affirm or withdraw the declaration” (21 USC § 342(f)(1)(C)). As
FCN which the FDA has not reviewed and in which the results with the significant or unreasonable risk of illness or injury stan-
are not clearly negative for carcinogenic effects. The FDA must dard, the government bears the burden to show that the dietary
apply the food additive general safety standard in its risk assess- supplement or dietary ingredient is adulterated. The net effect
ment of a food contact substance. (See 21 USC §§ 348(c)(3)(A), of these new standards is significantly less demanding than the
348(h)(1), 348(h)(3)(A); 21 CFR § 170.100(9c)(1).) reasonable certainty of no harm under the conditions of intended
Dietary supplements and dietary ingredients for dietary supple- use and wholly at variance with the legal framework for food and
ments. The DSHEA amended the FD&C Act to define dietary color additives addressed earlier.
supplements and prevent regulation of such products as food ad- Pesticide chemical residues. Before a pesticide chemical may
ditives. Consequently, a dietary supplement is a product (other be sold or distributed in the United States, the EPA must evaluate
than tobacco) intended to supplement the diet that contains 1 or the pesticide and determine whether to grant a registration per-
more of the following dietary ingredients: mitting such sale and distribution under the Federal Insecticide,
r vitamin; Fungicide, and Rodenticide Act (FIFRA). The EPA also establishes
r mineral; a tolerance (that is, maximum residue level), or an exemption
r herb or other botanical; from the requirement of a tolerance, for the pesticide chemical
r amino acid; prior to its use on food crops. Under the FD&C Act, any pesti-
r dietary substance for use by man to supplement the diet by cide chemical residue in or on a raw agricultural commodity is
increasing the total dietary intake; and deemed unsafe, thereby rendering the food adulterated, unless
r concentrate, metabolite, constituent, extract, or combination exists a tolerance or an exemption governing such use of the pes-
of any of the aforementioned. (See 21 USC § 321(ff)(1).) ticide chemical exists. Minute residues of the pesticide chemical
Dietary supplement products must also be intended for inges- may be present in processed foods produced from treated agri-
tion as a tablet, capsule, powder, soft gel, gel cap, or liquid; cultural commodities. A pesticide residue in a processed food
labeled a dietary supplement; and not be represented for use as does not render the processed food adulterated if the pesticide
a conventional food or as a sole item of a meal or diet. (See 21 was applied to the raw agricultural commodity pursuant to a tol-
USC §§ 321(ff)(2); 350(1)(B).) erance, the residues in or on the commodity were removed to
The DSHEA also added new safety standards to the FD&C the extent possible under GMP, and the residue level in the pro-
Act specifically for dietary supplements. A dietary supplement cessed food does not exceed that allowed for the commodity.
or a dietary ingredient therein is deemed adulterated if the sup- Residues of metabolites or other degradation products of pes-
plement “presents a significant or unreasonable risk of illness ticide chemicals may not render a food adulterated as long as
or injury . . . under . . . conditions of use recommended or sug- certain conditions are met. If the pesticide applied to the com-
gested in labeling, or . . . if no conditions of use are suggested or modity is subject to an exemption, its residues in a processed
recommended in the labeling, under ordinary conditions of use” food do not render the processed food adulterated. While the
(21 USC §§ 342(f)(1)(A)). The FDA bears the burden of proof in EPA is responsible for establishing, modifying, and revoking or
court if it asserts that a dietary supplement is adulterated under suspending pesticide residue tolerances, the FDA is responsible
this safety standard. In banning ephedrine alkaloids, the FDA infor enforcing such tolerances in domestic and imported foods
terpreted the term “unreasonable risk” in the safety standard to other than meat, poultry, and certain egg products. (See 21 USC
mean “a relative weighing of the product’s known and reasonably §§ 342(a)(2)(B), 346a(a)(1), 346a(a)(2)(A).)
likely risks against its known and reasonably likely benefits” (FDA The 1996 Food Quality Protection Act (FQPA) amended both
2004). Furthermore, the FDA concluded that “in the absence of the FIFRA and the FD&C Act to establish a safety standard for
a sufficient benefit, the presence of even a relatively small risk pesticide chemical residues in food, and required EPA to reassess


existing pesticide chemical tolerances and exemptions under the significant risk” level (maximum lifetime risk of cancer of 1 in 1
new safety standard: million) determined through appropriate toxicological testing as
a benchmark for assessing acceptability of a regulatory method.
. . . ’safe,’ with respect to a tolerance for a pesticide chemical (See 21 CFR § 500.84(c).)
residue, means that . . . there is a reasonable certainty that
no harm will result from aggregate exposure to the pesticide Presence of poisonous or deleterious ingredients
chemical residue, including all anticipated dietary exposures The FD&C Act provides a fail-safe provision that enables the
and all other exposures for which there is reliable informa- FDA to act against substances that are not subject to premarket
tion. (See 21 USC §§ 346a(b)(2)(A)(ii), 346a(c)(2)(A)(ii).) approval by or notification to the agency and that present a risk to
human health when present in food. The FD&C Act deems a food
To apply the FQPA safety standard, the EPA refined its existing adulterated if it bears or contains any poisonous or deleterious
risk assessment methods and added some new risk assessments. substance that may render it injurious to health. However, in case
For example, the EPA considers the following to establish, modify, the substance is not an added substance, such food shall not be
or revoke a tolerance or an exemption:
r the validity and reliability of available data from studies on the consideredin such food does not ordinarily render it injurious to
substance
adulterated under this clause if the quantity of such

pesticide or its residues; health. (See 21 USC § 342(a)(1).)
r any toxic effects shown in such studies; The FDA has frequently relied on this provision to regulate the
r the relationship of pertinent study results to human risk; presence in food of environmental contaminants such as lead,
r the dietary consumption patterns of consumers and major mercury, dioxin, and aflatoxin (FDA 1992). There are thus 2 sep-
identifiable subgroups;
r the cumulative effects of such residues and other substances arate and distinctsubstance has been “added”applied, depending
upon whether a
safety standards that may be
to a food or not. If
having a common mechanism of toxicity; an added substance, a poisonous or deleterious substance causes
r the aggregate exposure levels of consumers and major identi- the food to be adulterated if the substance may render the food
fiable subgroups to residues and related substances, including injurious to health. If the substance is not added, it renders the
dietary exposure under tolerances in effect or from nonoccu- food adulterated if the quantity that is present would ordinarily
pational sources;
r the variability of sensitivities of major identifiable consumer render and food injurious to health. The FD&C Act also deems
unsafe
the
therefore adulterated foods containing an added poi-
subgroups; sonous or deleterious substance (other than a pesticide chemical
r information on possible effects similar to estrogenic or other residue, a food additive, a color additive, or a new animal drug)
endocrine effects; and
r safety factors considered appropriate for reliance on animal at levels that exceed an FDA-established346.)
substance. (See 21 USC §§ 342(a)(2)(A),
tolerance level for such

data by food safety experts. (See 21 USC § 346a(b)(2)(D)(i)- Added substances. While the FD&C Act does not define the
(ix).) term “added,” the courts have interpreted the term to require
In particular, the EPA must also assess any risk to infants and some demonstrable human intervention to render a substance
children associated with aggregate exposure to the pesticide added. In United States v. Anderson Seafoods Inc., the 5th Circuit
residue. With respect to use, the EPA must consider whether U.S. Court of Appeals held that the term “added” as used in 21
use of the pesticide protects consumers from adverse health ef- USC § 342(a)(1) means artificially introduced or attributable in
fects that would pose a greater risk than dietary risk from the some degree to the acts of man. The court determined that some
pesticide residues and whether use of the pesticide is necessary mercury in fish is an added substance because it is not naturally
to avoid significant disruption in domestic production of an ade- produced by fish and becomes a component of the fish through
quate, wholesome, and economical food supply. (See 21 USC §§ contamination of its habitat by man. The court acknowledged that
346a(b)(2)(B)(iii), 346a(b)(2)(C).) part of the mercury in fish may occur naturally and is thus not
Animal drug residues in food-producing animals. In general, the added but concluded that where some portion of a toxin has been
FDA must approve new animal drugs as safe and effective for the introduced into the food by man, the entirety of that substance
intended use in animals, and food produced from such animals in the food will be treated as an added substance for purposes
must be safe for human consumption. The new animal drug ap- of the safety standard. (See United States v. Anderson Seafoods
proval provisions in the FD&C Act include a Delaney Clause pro- Inc., 622 F.2d 157, 159–61 (5th Cir. 1980); U.S. v. Blue Ribbon
hibition of FDA approval of animal drugs shown to induce cancer Smoked Fish Inc., 179 F. Supp. 30 (E.D. N.Y. 2001); Continental
in man or animals, as well as a DES Proviso exception from the Seafoods Inc. v. Schweiker, 674 F.2d 38 (D.C. Cir. 1982).)
prohibition. As mentioned earlier, the DES Proviso allows FDA FDA regulations define an added poisonous or deleterious sub-
approval of use of a carcinogenic compound in food-producing stance as one that does not naturally occur. In contrast, a natu-
animals, notwithstanding the food additive, color additive, and rally occurring poisonous or deleterious substance is “an inherent
animal drug Delaney Clauses, if the compound does not ad- natural constituent of a food and is not the result of environmen-
versely affect the animal under the conditions of intended use tal, agricultural, industrial, or other contamination” (21 CFR §
and if no residue of the compound would be found in the edible 109.3(c)). If the presence of a naturally occurring poisonous or
tissues after slaughter or in food from the live animal by an FDA- deleterious substance is increased to abnormal levels through
approved analytical method. (See 21 USC §§ 360b, 360b(d)(1)(I).) mishandling or other intervening acts, the substance may be ren-
For a carcinogenic compound to be approved under a DES dered an added substance to the extent of such increase. The FDA
proviso, any residue in the target tissue must be nondetectable “regards any substance that is not an inherent constituent of food
or below the limit of detection (LOD) of the approved regulatory or whose level in food has been increased by human intervention
method (FDA 2002). The FDA defines the LOD as the lowest con- to be ‘added’ within the meaning of section (342(a) (1))” (FDA
centration of analyte that can be confirmed by the approved reg- 1992). The agency views “a naturally occurring toxicant whose
ulatory method, and the “regulatory method” as the aggregate of level is unintentionally increased by the genetic modification,
all experimental procedures for measuring and confirming pres- as well as an unexpected toxicant that first appears in the food
ence of the marker residue of the carcinogenic compound in the as a result of pleiotropic effects” to be added substances (FDA
target animal tissue (21 CFR § 500.82(b)). The FDA uses the “no 1992).

For an added substance, the FDA need only show that the ical innovations, and international food standards. As considera-
substance could render the food injurious to health. The “could tion of food and food ingredient safety is increasingly broadened
render” standard means that the possibility of injury to the con- to the international stage, questions arise: Who undertakes food
sumer is reasonable. It does not mean that there must be abso- safety matters? Through what procedures and under what author-
lute certainty that no one under the most extreme circumstances ity does this occur? How are food chemical safety determinations
could be harmed. The U.S. Supreme Court acknowledged in the applied across multiple countries?
court case U.S. v. Lexington Mill that “(a) very large majority of
the things consumed by the human family contain, under analy- Codex Alimentarius Commission
sis, some kind of poison,” but the determination of whether the In 1963, the United Nations’ Food and Agriculture Organiza-
substance is dangerous depends upon the quantity and combi- tion (FAO) and the World Health Organization (WHO) created
nation. The Supreme Court further stated that if a food could not the Codex Alimentarius Commission, an international food stan-
by any possibility injure the health of any consumer, such food, dards setting organization that develops international food stan-
though having a small addition of poisonous or deleterious ingre- dards and codes of practice to protect consumers’ health and
dients, could not be condemned under the FD&C Act. The safety facilitate fair practices in international trade in food. These var-
standard is one of a reasonable possibility of injury to health. ious standards and practices comprise the Codex Alimentarius
(See U.S. v. Lexington Mill & Elevator Co., 232 U.S. 399 (1914); (the food code). It includes standards for food additives, con-
United States v. Anderson Seafoods Inc., 622 F.2d 157, 159-161 taminants, and toxins in foods that contain both general and
(5th Cir. 1980); U.S. v. Anderson, 447 F. Supp. 1151, 1155 (N.D. commodity-specific provisions as well as guidance on a variety of
Fla. 1978).) food subjects and issues (FAO-WHO 2006) (Table 1). The United
If an added poisonous or deleterious substance—other than Nations recognized the importance of the Codex Alimentarius in
a pesticide chemical residue, food additive, color additive, or addressing food safety internationally in 1985 when it passed Res-
new animal drug—is required or unavoidable under current good olution 39/248, which states, “When formulating national poli-
manufacturing practice, and if the FDA has established a toler- cies and plans with regard to food, Governments should take into
ance level for use of such substance, then food containing the sub- account the need of all consumers for food security and should
stance will not be deemed adulterated, provided such substance support and as far as possible adopt . . . standards from the Codex
is present in the food in an amount below the tolerance level. Alimentarius” (CAC 2009). More recently, the Sanitary and Phy-
The FDA has discretion in deciding whether to establish a toler- tosanitary Measures Agreement (SPS Agreement) of the Uruguay
ance level, which requires formal notice-and-comment rulemak- Round of GATT requires World Trade Organization (WTO) mem-
ing and prefers to employ informal guidance levels (also known bers to base their sanitary and phytosanitary measures on interna-
as action levels) instead. Action levels are enforcement discretion tional standards and to participate in Codex. The SPS Agreement
guides that do not have the force of law, but rather inform industry specifically recognizes Codex texts as the international bench-
that FDA generally will not enforce the FD&C Act’s adulteration mark. The revised Technical Barriers to Trade Agreement also
provisions with respect to an affected substance provided that references Codex texts. Thus, the Codex Alimentarius and stan-
the level of the necessary or unavoidable added poisonous or dards within it directly affect food safety and international food
deleterious substances present in food remains below the estab- commerce and are an integral part of the legal framework within
lished action level. Both tolerances and action levels are based which international trade is being facilitated through harmoniza-
on unavoidability; they do not establish a permissible level of tion (FAO-WHO 2006).
contamination when such level is avoidable (21 CFR § 109.7(a)). Codex is truly global in nature since membership is open to all
(See 21 USC § 342(a)(2)(A); Young v. Community Nutrition Inst., member nations and associate members of FAO or WHO. Mem-
476 U.S. 974 (1986).) ber nations span the range from those that are highly developed
Not-added substances. Because the FDA defines a naturally oc-
curring poisonous or deleterious substance as an inherent natural
constituent of the food that is not present due to environmental, Table 1 --- Standards and other guidance comprising the
agricultural, industrial, or other contamination, bones in fish and Codex Alimentarius.
oyster shell fragments are deleterious substances within this cate-
gory. Potentially poisonous amygdalin, which is present naturally Type of Guidance Number of Texts
in apricot kernels and numerous other fruits, vegetables, grains,
Commodity standards 186
and seeds, is another example of a not-added substance. The
Commodity-related texts 46
safety standard applied to such nonadded substances is whether
Food labeling 9
its presence ordinarily renders the food injurious to health. Courts
Food hygiene 5
interpret the standard to mean ordinary uses under ordinary con-
Food safety risk assessment 3
ditions. This standard is more relaxed than the “render injurious”
Sampling and analysis 15
standard applicable to added substances. (See U.S. v. 1232 Cases
Inspection and certification procedures 8
American Beauty Brand Oysters, 43 F.Supp. 749 (W.D.Mo. 1942);
Animal food production 6
Millet, Pit and Seed Co. Inc. v. United States, 436 F. Supp. 84 (E.D.
Contaminants (maximum levels, 12
Tenn. 1977).)
detection, prevention)
Food additive provisions 1112 (addressing
International Framework 292 additives)
Although the FD&C Act provides the fundamental framework Food additive-related texts 7
for food chemical safety assessments in the United States, the Pesticides (maximum residue limits) 2930 (addressing
food industry must consider a more global perspective because it 218 pesticides)
serves and operates in international markets. The globalization of Veterinary drugs (maximum limits) 441 (addressing
the food supply and the safety of foods and their constituents war- 49 veterinary drugs)
rants that international commerce be addressed by agencies and Regional guidelines 3
organizations that keep pace with scientific advances, technolog- Source: FAO-WHO 2006.



to newly emerging. Nearly 99% of the world’s population is rep- Codex derives great value from the JECFA and the JMPRs since
resented in the commission through approximately 174 member a broad cross-section of technical disciplines—biochemistry,
countries and 1 member organization (the European Commu- chemistry, food science and technology, physiology, pharma-
nity) (FAO-WHO 2006). In addition to government delegations cology, toxicology, and pathology—is represented on the advi-
in Codex matters, nongovernmental organizations (NGOs) also sory groups, and selected experts are preeminent, impartial, and
contribute to deliberations, participating as observers. NGO dele- objective.
gations represent consumer organizations, the food industry, and JECFA safety assessments and evaluations. During the last 50
scientific associations (for example, IFT). years the JECFA has evaluated more than 1500 food additives,
The Codex system involves standing committees that are gen- around 40 contaminants and naturally occurring toxicants, and
eral subject (such as Codex Committee on Contaminants in residues of about 90 veterinary drugs (FAO-WHO 2006). Two
Foods) or commodity (such as Codex Committee on Fish and Fish- important points about food chemicals are considered during
ery Products) in nature, regional coordinating committees, ad hoc JECFA safety evaluations: (1) most food components and addi-
task forces, a variety of collaborative activities, expert consulta- tives are consumed at low levels in humans, possibly over an
tions, and expert advisory committees. To develop standards and entire lifetime; and (2) toxicology studies are conducted at ex-
other guidance texts such as those addressing the safety of food aggerated doses that use concentrations, routes of exposure, and
additives, Codex follows a transparent, defined, and often lengthy shorter periods of exposure that may not realistically reflect the
8-step process upon acceptance of a specific proposed project anticipated human experience with the food chemicals in ques-
by the commission or executive committee. This process is some- tion. The JECFA, the JMPRs, and the Intl. Programme on Chemical
what akin to a notice-and-comment rulemaking procedure used Safety (IPCS) have developed principles) for the safety assessment
in the United States. To be sure, the scope and amount of informa- of food additives and contaminants and toxicological assessment
tion arising on food chemical safety topics can be formidable and of pesticide residues in food.
far-reaching. This is often the case when Codex considers food The JECFA evaluates the toxicology and broad composite sci-
ingredient standards and key characteristics, such as maximum entific information that is available and extrapolates the findings
use levels and the presence of undesirable components such as to arrive at an exposure that is considered to be safe for humans.
contaminants. During deliberations, questions often arise regard- This composite of information includes data and information sub-
ing whether the interpretations of the cited studies are accurate mitted by interested parties in response to specific calls for data
and whether the quality and quantity of science are sufficient to published by the JECFA. It is incumbent on interested parties to
support the recommended positions potentially emanating from compile and submit for evaluation comprehensive scientific data
Codex. In addition to safe use levels and material purity, methods for JECFA review. Such information includes the following:
of analysis within a food matrix must be addressed. r composition of the material(s) in question, including specifi-
In utilizing the committee structure, Codex subsidiary bodies cations for purity and identity that reflect the material that is
draft texts ultimately yielding monographs that are then circu- subject to toxicology testing;
lated to member countries, NGOs, and other interested parties. r appropriate safety studies from humans and experimental ani-
If warranted from the reviews, revisions are generated, which of- mals; and
ten involve further deliberation in preparation for final adoption. r identification of food chemical applications, associated food
Although the Codex philosophy embraces harmonization, con- use levels, and estimations of probable human intake.
sumer protection, and facilitation of international trade, it can be The JECFA commonly applies safety factors, as the FDA does in
difficult for countries to accept Codex standards in the statutory its safety assessments, to account for uncertainties and limitations
sense because of different legal formats, technical infrastructure, surrounding available scientific data as well as the experimental
administrative systems, and various political systems (FAO-WHO design limitations associated with the conduct of safety testing
2006). regimens. For chemical contaminants, the JECFA introduced the
Expert advisory committees. Of great importance to Codex de- margin of exposure (MOE) approach developed by the European
liberations and national regulatory authorities is the work of Food Safety Authority (EFSA) (2005). When considering inten-
scientific advisory bodies to the Codex Alimentarius Commis- tional food additives, safety factors of at least 100 are commonly
sion, FAO, and WHO and expert consultations. Of the 3 main applied to a no-observed-effect level (NOEL) that is determined
FAO/WHO expert advisory bodies, 2 relate to food chemical experimentally. The hundredfold safety factor reflects a tenfold
evaluation and assessment. The Joint Expert Committee on Food variation in sensitivities within a given test species along with
Additives (JECFA), established in 1955, advises primarily through another tenfold variation in extrapolating from test animal ex-
the Codex committees on food additives, contaminants, and periences to man. In the absence of satisfactory safety data, the
residues of veterinary drugs in foods. These committees determine JECFA may also impose an additional safety factor as prompted
the food additives, contaminants, and veterinary drug residues by any safety concerns and judged against the available scientific
JECFA should assess, enabling the work leading to their incor- data.
poration into Codex standards. Established in 1963, the Joint By considering the accumulated animal data and any avail-
FAO/WHO Meetings on Pesticide Residues (JMPRs) recommend able human studies, the JECFA determines an ADI that is usually
maximum residue limits (MRLs) for pesticide and environmental expressed in terms of milligrams of substance per kilograms of
contaminants in specific food products to ensure the safety of body weight per day. If the accumulated scientific information
foods containing residues and methods of sampling and analysis. is insufficient or incomplete, the reliance on safety factors larger
The JMPRs work closely with the Codex Committee on Pesticide than 100 may be required, which, in turn, may yield an ADI for
Residues, which identifies substances that need evaluation prior the subject material that is below the estimated consumer expo-
to considering and determining acceptable MRLs for the com- sure. When this occurs, either the proposed food uses must be
mission to consider adopting. restricted to reduce the estimated consumer exposure to a level
The input provided by these expert bodies is thus impor- that is less than the ADI or additional toxicology testing must be
tant when the Codex commission considers safety evaluations conducted to support an increased ADI that would exceed the
of food additives, food contaminants, animal drug and pesti- estimated consumer exposure to the subject additive. However,
cide residues, and other food components and when it devel- care must be exercised when considering the reduction of the
ops specifications and adopts acceptable methods of analysis. proposed additive use level to better align with a calculated ADI

since doing so could result in too low a level to achieve the for determining the extent of risk management actions that are
intended technological effect. necessary.
In addition, the JECFA estimates the consumer exposure or Transparency and effective consultation with stakeholder
probable daily intake of the substance in question, which is groups are essential elements for regulatory authorities to build
subsequently compared to the ADI. If the ADI is higher than external confidence in their actions. Consumer awareness and
the consumer exposure estimate, the additive is deemed to be demands on food matters are high in European countries. Com-
safe for its intended uses. The JECFA findings are shared with munication, evaluation, and explanation of potential risks, in-
the CCFA, which translates the JECFA assessment into a maxi- cluding full transparency of scientific opinions, are important for
mum allowable concentration of substance in food. Alternatively, EU authorities and are expected by EU consumers. Consumer
the Codex committee may determine that a maximum level is confidence is a primary goal for EU actions on food. Therefore,
unnecessary. the EFSA has established guidance on general principles of scien-
On occasion, the JECFA safety deliberations may yield an ADI tific transparency for the scientific aspects of risk assessment. In
that is not specified. Such a finding does not mean that the ad- addition, the EFSA follows the general risk assessment principles
ditive in question may be used in foods in any amount; instead, of Codex and has elaborated its guidance while also consulting
the JECFA and Codex ascribe to the principle that additives are with external stakeholders.
to be incorporated into foods at the minimum levels needed to The European Commission develops EU legislation for man-
achieve desired technological effects and no more. Those addi- aging food safety risks in conjunction with government repre-
tives that receive assigned ADIs of not specified exhibited very sentatives of its member states and consults with stakeholders
low toxicities on the basis of available science and the projected such as industry and consumer groups. The European Commis-
total dietary intake of the substance when added to foods at the sion proposes framework legislation to the European Council and
minimum level that achieves the desired technological effect. Parliament. Within frameworks, the European Commission may
Such use does not constitute a hazard to consumer health. Con- often develop separate technical legislation without further con-
sequently, the JECFA regards the establishment of a numerical sulting the council and parliament. The framework approach for
ADI as unnecessary for these additives. regulating chemical contaminants is a good example to con-
sider. Chemical contaminants are regulated under the framework
The European Union of Council Regulation 315/93, which gives the European Com-
Many governments around the world maintain national control mission the authority to establish separate legislation within the
systems that affirmatively address chemical food safety matters framework, including setting maximum levels on specific con-
based on their own laws and regulations. The European Union taminants. In the EU, a number of regulations have addressed
(EU) has been particularly active in setting laws and standards on levels of contaminants in foods and these regulations are consol-
chemical food safety. During recent years, the differing laws and idated in Commission Regulation 1881/2006.
degrees of law on food safety that existed in individual EU mem- Determining acceptable safe levels is an issue facing all regu-
ber countries, or member states, have been harmonized under latory authorities. Credible levels must be based on sound prin-
common European law. These laws have set standards for food ciples. Scientific and other considerations are necessary to deter-
produced in and imported into EU member states. Other coun- mine what satisfies the risk assessment advice and what is feasible
tries around the world have been influenced by these standards, and reasonably achievable in commercial practice. The EU fol-
whether for compliance of foods and food ingredients for export lows the as-low-as-reasonably-achievable (ALARA) principle of
to EU member states or because national governments elsewhere decision-making. A difficulty and point of reservation for some
decided to develop similar standards for local use. EU standards groups on the ALARA principle is how to define “reasonably”
often set a precedent for wider discussions on global standards in each case to ensure that reasonably achievable levels are in-
such as Codex. deed “reasonably achievable,” based on good practices that are
Regulation 178/2002 consolidated an integrated farm-to-fork possible in commercial practice. For stakeholder consultations,
approach as a general principle for EU food safety policy. This the availability of data for ALARA-based levels is imperative. This
general food law regulation recognizes international obligations ensures that regulators have information to address any practical
and takes into account international standards. However, inter- difficulties, and supports food safety protection without present-
national standards do not always exist or may be insufficient for ing an unreasonable burden for food production.
EU consumer protection expectations. For risk assessors, one category of food chemicals that is not
The EU Food Law adheres to the 3 well-recognized compo- straightforward when providing useful advice to risk managers is
nents of risk analysis: risk assessment, risk management, and risk genotoxic carcinogens. Genotoxic carcinogens are considered
communication. Risk management actions are based on a scien- to have no threshold of safety, potentially causing direct ad-
tific risk assessment but also take into consideration a wide range verse effects on DNA. Therefore, no tolerable exposure levels
of other factors such as consumer information, prevention of mis- can be set, which would otherwise help determine safe levels
leading practices, feasibility of controlling a risk, most effective of dietary intake. To promote more useful advice on genotoxic
risk reduction actions for the relevant part of the food supply contaminants and substances found in food, the EFSA developed
chain, practicalities, socio-economic effects, and environmental an MOE approach. This considers the margin between doses
impact. shown in experimental studies to cause adverse effects and the
The risk assessment process in the EU was transferred in 2002 amounts eaten by consumers. This gives an indication of how
from the European Commission and its Scientific Committee on close human dietary intake is to levels shown to cause toxic ef-
Food to the EFSA under the EU Food Law. This gave risk assess- fects in the laboratory. With this logic, it is important to ensure
ment more independence and visibility in the EU. The EFSA has a that the available data set on sources of dietary exposure is as
number of independent scientific panels made up of technical ex- complete as possible. Dietary exposure estimates must be based
perts in various fields. When an issue arises that requires scientific on consumers of the food and not on entire populations, as many
risk assessment, the risk managers at the European Commission people may never eat the food substance in question. More-
forward a technical request to the EFSA or the EFSA will self-task over, consumers of average levels must be taken into account
for an assessment by the respective scientific panel. The European as well as consumers who regularly eat higher amounts of the
Commission then uses the EFSA assessment as the scientific basis foods.


If the MOE is small, then risk management action is more likely harmonizing the laws of the member states on matters related to
to be necessary, particularly if all major sources of dietary intake consumer safety, as was the case with additives.
are not understood. In some cases, even if the MOE is high over- This legal background changed significantly in 1993 when the
all but poor practices are known to cause high contamination Maastricht Treaty modified the EC Treaty of 1957 by adding sev-
in certain products, then risk management action is likely to be eral new titles, including public health, consumer protection, and
necessary to address problems. For example, direct heating from environment. A new general obligation was also imposed on the
inappropriate fuel sources in poorly controlled environments commission: to “take as a base a high level of protection” in all
caused very high levels of polycyclic aromatic hydrocarbons. In its proposals concerning health, safety, environmental protection,
response, the EU developed maximum levels for polycyclic aro- and consumer protection (article 100.3(95.3), EC Treaty). At the
matic hydrocarbons. Clearly, for undesirable chemical contami- same time, article 130r(174) relating to environment was intro-
nants not intended for use in food production, no authorization duced. This article states, “Community policy on the environment
process is involved in their regulation. However, for substances shall aim at a high level of protection taking into account the di-
that are intended for use in food production, different regulatory versity of situations in the various regions of the Community. It
processes apply. shall be based on the precautionary principle and on the princi-
Additives have technological functions in food and their need ples that preventive action should be taken, that environmental
and safety must be demonstrated. They must therefore be autho- damage should a priori be rectified at its source and that the
rized for specific uses at predetermined levels based on func- polluter should pay.” Although the precautionary principle was
tionality and safety assessment data. A complicating factor with initially stated only in provisions of the treaty related to environ-
additives is that there is often need for further safety evaluation ment, it was eventually implemented as a basic principle of food
even after authorization. Re-evaluation is sometimes necessary law, backed by the European Court of Justice (ECJ), and is now
to respond to new scientific publications—hence the fluctuating well-embedded in food law.
views on some commonly used additives that can sometimes be The first step in applying the precautionary principle to foods
raised in the media. Similarly, pesticides are controlled based on occurred in the context of the bovine spongiform encephalopa-
their agricultural function and safety to ensure that residues in thy (BSE) crisis that erupted in 1996. In the case Natl. Farmers
food are kept to a minimum. The threshold of safety for intake Union, the ECJ concluded that “where there is uncertainty as to
of a given pesticide is often considerably higher than the likely the existence or extent of risks to human health, the institutions
exposure based on the legal MRLs authorized in food materi- may take protective measures without having to wait until the re-
als. This approach aims to encourage good agricultural practices ality and seriousness of those risks become fully apparent.” The
(GAPs) and control the application of pesticides and the total ECJ further stated, “That approach is borne out by Article 130r(1)
residues in food. MRLs also help indirectly control residues in of the EC Treaty, according to which Community policy on the
the environment; however, specific legislation applies for en- environment is to pursue the objective inter alia of protecting hu-
vironmental residues. Environmental residue limits cannot be man health.” Article 130r(2) provides that the policy is to aim at a
transposed to food items because the science and practicalities high level of protection, be based on the principles of preventive
are very different. Whenever MRLs are set for any pesticide in action, and integrate environmental protection requirements into
food, it is important that they are calculated based on GAPs the definition and implementation of other community policies.
in the growing region for the particular raw ingredients to be (See Natl. Farmers Union, ECJ C-157/96 (May 5, 1998).)
consumed. Several other subsequent judgments confirmed this approach
If any country decides to adopt a standard similar to one set by and explicitly quoted the precautionary principle in areas other
another country, the precise context for the standard, local im- than the environment, particularly in food and feed. For exam-
plications, and feasibility of adopting that standard must be un- ple, in the case Pfizer Animal Health, which was related to an
derstood, based on what is known and what needs to be known authorization procedure for an animal feed substance, the Court
about local products. For example, when the EU sets a standard, of First Instance (CFI) asserted that “the Community Institutions
it takes into account thorough investigation of available data and may, by reason of the precautionary principle, take protective
good production practices for the implicated food substance as measures without having to wait until the reality and seriousness
consumed in the EU. However, for the same food substances of those risks become fully apparent.” This judgment along with
consumed in a different country, there could be differences in court decisions rendered during the same time period and subse-
the way the substance is used, produced, or consumed that may quently by the ECJ and the CFI founded all the basic rules for the
have implications on what is reasonable to achieve locally. Local enforcement of the precautionary principle and the conditions for
authorities must understand such differences and generate local its use. (See Pfizer Animal Health, CFI 1-13/99 (Sept. 11, 2002).)
data. When common international standards are being devel- In parallel to the ECJ and CFI decisions, European Community
oped, countries can use the global Codex forum to input their institutions adopted a basic text on food law, Reg. 178/2002, in
local information to develop and promote standards that would which for the first time, food as well as food law were defined,
be reasonably achievable on a global front, taking into account establishing the general principles and requirements of food law,
their local knowledge. the EFSA, and procedures in matters of food safety. Accordingly,
food safety has become one of the cornerstones of food law
The precautionary principle regulation, and the precautionary principle has become one of
When the Rome Treaty was adopted in 1957, the regime of its basic principles in the EU.
food products was influenced by 2 main sets of rules, the Com- Noting that “Food Law shall pursue one or more of the gen-
mon Agricultural Policy (CAP) and the general principle of free eral objectives of a high level of protection of human health and
movement of goods within the European Community. Techni- the protection of consumer’s interests” (article 5.1, EC Treaty), the
cally, there was no food law; however, ensuring safety of the regulation documents the principles of risk analysis and mentions
consumer was contemplated both by the CAP, which included the precautionary principle as a tool for risk management. Articles
hygiene and veterinary rules, and by the enforcement of the free 6 and 7 must be interpreted together to understand how Euro-
movement of goods principle, which allowed member states to pean Community law now regulates decision-making regarding
prohibit imported products for the protection of public health. For food safety when the science is incomplete. As to risk analysis,
this reason, some European Community directives were aimed at the treaty states, “Risk assessment shall be based on the available

scientific evidence and undertaken in an independent, objective of a measure based on the precautionary principle depends not
and transparent manner”(article 6.2, EC Treaty), and “risk man- only on the fact that uncertainty persists but also that the research
agement shall take into account the results of risk assessment, goes on even after said measure has been taken. Furthermore, ar-
and in particular, the opinions of the EFSA referred to in article ticle 7.2 of the EC Treaty explicitly states that the measure should
22, other factors legitimate to the matter in consideration and be reviewed “within a reasonable period of time.” A permanent
the precautionary principle where the conditions laid down in precautionary measure would be illegal if no effort were made to
article 7.1 are relevant, to achieve the general objectives of food clarify the scientific situation.
law established in article 5” (article 6.3, EC Treaty). Is it therefore The measures taken under the precautionary principle must
clear that the precautionary principle is a tool for risk manage- be proportionate and constitute the strongest protection against
ment and does not intervene at the risk assessment stage, which misuse of the principle. Proportionality is a general principle of
is entirely within the competence of science? European Community law in which any measure imposing obli-
As to the precautionary principle and the conditions of its use, gations on operators should be limited to that which is strictly
article 7 states, necessary to achieve the objective of a measure (provided also
that the objective itself is recognized as legitimate). This general
principle is a very effective tool enforced by the ECJ and the CFI
In specific circumstances where, following an assessment of
for controlling measures by public authorities under European
available information, the possibility of harmful effects on
Community law. In assessing the proportionality of the measure,
health is identified but scientific uncertainty persists, pro-
regard should be given to technical and economic feasibility.
visional risk management measures necessary to ensure the
Technical and economic feasibility are not the only elements to
high level of health protection chosen in the Community may
be taken into account; importantly, the objective of the measure
be adopted, pending further scientific information for a more
should be to ensure a high level of protection. The level of protec-
comprehensive risk assessment.
tion is of a political nature and therefore cannot be challenged as
Measures adopted on the basis of paragraph 1 shall be pro- such in court whereas the adequacy of the measure undertaken
portionate and no more restrictive of trade than is required to ensure this protection can be challenged in court.
to achieve the high level of health protection chosen in the Pursuant to separation between risk assessment and risk man-
Community, regard being given to technical and economic agement authorities, risk assessment authorities are not entitled
feasibility and other factors regarded as legitimate in the to invoke the precautionary principle. Their duty is to indicate
matter under consideration. The measures shall be reviewed when science is incomplete, but they should not suggest the mea-
within a reasonable period of time, depending on the nature sures to be undertaken. Under European Community law, these
of the risk to life or health identified and the type of scientific measures are undertaken by the authorities and can be based
information needed to clarify the scientific uncertainty and on all legitimate factors, including scientific risk assessment. The
to conduct a more comprehensive risk assessment. other legitimate factors are not scientific but include consider-
ations of environmental or public order. It would therefore be
This text was adopted in 2002, several years after the precau- illegal for an authority to invoke the precautionary principle in
tionary principle was first mentioned in the context of food law support of a measure undertaken on the basis of legitimate fac-
and after long debates within the EU and internationally, par- tors other than scientific uncertainty. Indeed, for any measure to
ticularly in Codex. Much of the debate has subsided since the be legal, it should be clearly motivated and consistent with its
text of Regulation 178/2002 takes into account the case law of motives.
the ECJ and the CFI and delineates clear limits to the use of the
precautionary principle. However, not all problems and misun-
derstandings have vanished. Risk Analysis
According to Regulation 178/2002, the precautionary princi- Risk science has emerged as a powerful tool to aide in safety as-
ple is a tool for risk management to be used by those who make sessment decision-making, and application of risk analysis tech-
food law (that is, regulatory authorities). It does not create obli- niques is progressing around the globe. The U.S. Natl. Academy
gations bearing directly on private operators. The responsibilities of Sciences defines risk analysis as a paradigm involving 3 ma-
of private operators are addressed in articles other than articles 6 jor steps: research, risk assessment, and risk management (NRC
and 7 in Reg. 178/2002 (see art. 14 to 21). It is obvious that since 1983). Since then, The Codex Alimentarius Commission and
the precautionary principle may govern decisions made by the WHO have defined risk analysis as a process comprising 3 key
public authorities, private operators must remain cognizant of it components: risk assessment, risk management, and risk commu-
and would be well advised to take it into account when making nication (CAC 1997, 2003a, 2007). In addition, Codex defined
management decisions. However, there is an ongoing debate as each of the 3:
to whether failure to act according to the precautionary principle r Risk assessment consists of 4 steps: hazard identification, haz-
would provide a basis for suing or condemning an operator. Thus ard characterization, exposure assessment, and risk character-
far, there is no precedent in the case law that would impose a ization.
penalty on an operator based on the precautionary principle. r Risk management is the process, distinct from risk assessment,
By definition, the precautionary principle does not apply when of weighing policy alternatives in consultation with all inter-
there is any doubt whatsoever about the safety of a product. The ested parties, considering risk assessment and other factors
precautionary principle is the response to the problem of incom- relevant for the health protection of consumers and for the
plete science and not just lack of information or doubt regarding promotion of fair trade practices and, if needed, selecting ap-
the accuracy of a process. Therefore it would be inappropriate for propriate prevention and control options.
an operator to rely on a precautionary principle alone to justify r Risk communication is the interactive exchange of infor-
a recall or restrictive measure as a way to benefit from the situa- mation and opinions (about risk, risk-related factors, and
tion when the science is incomplete. Moreover, risk management risk perceptions) throughout the risk analysis process among
measures taken on the basis of the precautionary principle are risk assessors, risk managers, consumers, industry, the aca-
provisional, and further scientific information is necessary for a demic community, and other interested parties (CAC 2003a,
more comprehensive risk assessment. This means that the legality 2007).

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